Letrozole is superior in live birch rate over clomiphen

Q.1 Prevalence of infertility in women & PCO??  Female factors are responsible for 40%-50% of infertility cases while the others are due to male causes as well as combined female/male causes and unexplained infertility .

As of 2003, female infertility (age-dependent) affected 7% to 28% of women  had PCO. PCO related  subfertility is very common scenario.

Q. 2:  Who conducted “The pregnancy in polycystic ovary syndrome ii (ppcos ii) trial? Ans: Researchers were Richard S. Legro, Allen R. Kunselman, [...], and for the NICHD Reproductive Medicine Network

” What was the design of the study??  : The design was “double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome”

 Sadly, there is a tendency to prescribe new drugs too early. It has become a  fashion in last five decades !!! Are we adopting new drugs and changing our old drugs too prematurely before firm robust evidences are available. For instance which drug to choose first as ovulatory agent?

Q.3: What was the goal of the “Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) study ? Ans:-  It was  to determine the safety and efficacy of clomiphene citrate (CC) compared to letrozole, in achieving live birth in infertile women with PCOS.

Q. 4:- What’s wrong with CC??? Why new study in PCO & subfertility when a safe agent like CC is available?? Ans:-What is wrong with CC?? , CC results in both a high nonresponse rate and multiple pregnancy rates. These limitations resulted in  a relatively low success rate (only 23% had a live birth in the CC group of the PPCOS trial and a further 25% never had a single documented ovulation during the study period), concern about multiple pregnancies (4–6% multiple pregnancy rate with one triplet gestation in the CC containing arms), and possible adverse effects of CC (including visual changes, ovarian hyperstimulation syndrome, and pelvic pain likely due to ovarian cyst formation). Other limitations include estrogen antagonism on target organs, such as potential thinning of the endometrium and decreased efficiency of embryo implantation, and concern about the long half-life and effects of accumulated CC metabolites on ovulation and pregnancy, including the possibility for fetal teratogenic effects.  Many women also experience vasomotor symptoms, including hot flushes, headaches, and mood changes during treatment with CC that limit its use .

Proposition :--Legro considerd that Aromatase inhibitors such as letrozole may have more favorable ovarian and endometrial effects.

Q. 5 :What were the lacunae/ shortcomings  in What was wrong in  Pregnancy in Polycystic Ovary Syndrome (PPCOS I) study ?  Ans the study conducted by the Reproductive Medicine Network  the first study :-.  the  goal of prescribing CC/letrozole should have been  aimed  at   achieving a live birth .Unfortunately , this was not included was in that first study. .( Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551–566. [PubMed] [Google Scholar]).

Instead study concentrated on result outcome in CC vs Metformin in PCO and live birth rate was not evaluated.  This was the Deficincy of Pregnancy in Polycystic Ovary Syndrome (PPCOS I) study. CC was found to be three times more effective than metformin at achieving live birth, with no significant added benefit of the combination of metformin and CC.

However, the PPCOS I trial also highlighted the limitations of CC and the need for better ovulation induction agents.

Q. 6:--What are then advantages of Letrozole over CC ?? Aromatase inhibitors (AIs), primarily letrozole, have been promoted as potent ovulation induction agents These drugs were developed as adjunctive agents to treat breast cancer and they work as selective aromatase inhibitors, thus preventing the conversion of androgen to estrogen. The resulting altered sex steroid ratio may release the hypothalamic pituitary axis from inappropriate and excessive estrogen feedback (which in PCOS results primarily from peripheral conversion of elevated circulating androgens) and increase serum FSH levels, which would in turn encourage healthy ovarian follicular development. Third generation AIs can be given orally and are well tolerated (main side effects are GI disturbances, asthenia, hot flushes and back pain). Their half-life is around 45 h, significantly shorter than CC. Studies have shown that AIs improve endometrial thickness compared to CC and while multiple follicles are induced, multiple gestations appear to be less likely with AIs .These factors may lead to higher pregnancy rates and a greater likelihood of a singleton pregnancy.

What was very special in “The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) study protocol”- Lergo et al developed    a number of secondary research hypotheses including:  Aim 1) Treatment with letrozole is more likely to result in a singleton pregnancy compared to treatment with CC. Aim  2) Treatment with letrozole will less likely result in a first trimester intrauterine fetal demise than treatment with CC.   Aim :3) Treatment with letrozole is more likely to result in ovulation (increased ovulation rate) compared to treatment with CC.

 Aim 4) The shortest time to pregnancy will be with letrozole. Aim 5) Age, body mass index and serum sex hormone binding globulin (SHBG), testosterone, LH, Anti-Mullerian Hormone (AMH), and degree of hirsutism and acne will be significant predictors of ovulation and conception regardless of treatment. Aim 6) Improvement during treatment in serum levels SHBG, testosterone, AMH, and LH levels will be significant predictors of ovulation and conception regardless of treatment assignment. Aim 7) DNA polymorphisms in estrogen metabolism and target genes will predict response to study drug. Aim 8) Quality of Life will be better on letrozole than CC. Aim 9) Letrozole will be more cost effective at achieving singleton pregnancies than CC. Previous studies in this regard  have limited power to address many of these secondary hypotheses.